Racemic-alpha-hydroxy-beta, beta-dimethylgamma-butyro lactone, esters and salts thereof



thereof. M

I have discovered active isomers.

temperature.

Patented Aug. 31 1943 lemme-a mo -c,*c DIMETHYL- GAMMA-BUTYRO LACTONE,ESTERS AND SALTS'THEREOF i i Jacob Finirelstein, Ne

to Merck & 00., In I poration 01' J ersey wvYorlnN. YQ, assignor 0.,Railway, N. J., acor-- rroprawmg. Application July 3,1940,

n l SerialNo.343,779

4Claims. Cl.260- 344) This invention relates to racemic a-hydroXyfi,fl-dimethyl-gamma-butyrolactone, derivativesdimethylagamma-butyro1actone may be obtained by reactingisobutyraldehyde an'd formalin in the presence of an alkalimetalcarbonate at ,below f C., to form" 2,2- dimethyl propanol-3-ald,

treating the latter compound with HCN to form the corresponding nitrile,andtreatine the said I nitrile with concentrated hydrochlori'c acld toformthesaidlactone.

Thislactonemay be reacted with p-ammne to form pantothenicacid, avaluable growth Dromot-l ing substance, I y I have also discovered thatsalts or suchlactone {may bepreparedwhich are useful in thelresolutionof the racemic lact me into its optically 1 Example i Two hundred gri s.of isobutyraldehydeand 224 gms. of 40% formalin are mixed, and, whilestirring with cooling in'an ice bath, 160 gms. of,

potassium carbonateare added in small portions. During the reaction, itis essential that the temperaturefbe maintained below 20 C. After all ofthe potassium carbonate is addedpthemixture 9 which time the mixturebecomes viscous.

dried overanhydrous sodium sulfate.

. is stirred foran additional minutes, during Th product is extractedwithether, and the extract The :ether is distilled ofLiandtheviscousres- 132 ,gms. On recrystallization fromwater, 2,2-

crystalline solid, which when"recrystallized from alcohol and dryingover P2Os,"r nelts at 96-7 C.

Seventy-two gms. of 2,2 dimethyl propanol-Iial-l arewarmed and stirredwith a solutionoi' 80 gins. of sodiumbisulfite in 500 cc. water. Whenthe -aldol is all dissolved, the mixture is cooled to and maintainedat"0-10 C., and, while stirring, a solution of 46 gms. of potassiumcyanide in 100 cc. of water is addedslowly. The mixture is stirred for 1hour at1010 C. after all or the cyanide is added. The ice bath is thenremoved,

and the mixture stirred until it reaches room 1 The mixture isseparated, and the aqueous layer extracted with ether. The oily productand ether extracts ar Icombinjed, dried yield '13 gins.

A solution of 38 mic. or the above while in idue distilled at 15 mm,B.P. 83-86 C. Yield dimethyl propanol-3-al-1 is obtained as a white overanhydrous sodiumsulfate, filtered; and the etherevaporated. The nitrileis a viscous liquid,

cc. of other is added dropwise, while'stirring and keeping thetemperature at 10 15 C.,;to cc. or concentrated hydrochloric acid. Themixture is then allowed tostand overnight, d uring which time ammoniumchloride crystallizes out. 100 cc. of water are added, and the mixtureheated on the steam bath for 3 hours,during wh ich tim the ether isdistilledofi. The mixture is adjusted to pH 7.2 sodium bicarbonate, andextracted continuously withether for-[16 hours. The extracts arecombined, dried over sodium B. P. 121 at 10 mm. 3,fl-dimethylgamma-butyrolactone is a colorless liquid, which immediately solidifies,yield 26 gm,

and may be recrystallized from an ther'. tr leum ethermixture. i A r Amixture of 0.2471 gm. of racemic a-hydroxy-w)8,fl-dimethyl-gamma-butyrolactpne and 0.410-gm'. of p-nitrobenzenoylchloride is dissolved'i n' i cc dry pyridine, and heated at 100 for 1hour; 1 The solution is acidified to Congo red withdilute sulfuric acid,and theprecipitated solid dissolves in ether. The ethereal solution iswashed with sodiumlcarbonate solution, dried over sodium sulrate, theether removed in vacuo, and the p -nitrobenzoate ester of racemica-hydroxy-fl,p-dimethyl+gamma-butyrolactone recrystallized from alcoholas needles, M. P. 137-13 The camphorsulfonate of racemic-a-hydroxympdimethyl-gamma-butyrolactone may be prepared according to theabovementioned method by employing camphorsulfonic acid chloride as astarting material, M. P. 118-12050. Example III 1 Six and one-half gms.of a-hydroxy-c e-dimethyl-gamma-butyrolacetcne and 7.4 gms; of

powdered phthalic anhydride' are suspended, in

10 cc. of dry pyridine, andheated at 100 C. for

1 hours. The mixture is cooled, acidified with dilute hydrochloric acid,and the precipitate filtered'and recrystallized from butanol. M. P. of

the hydrogen phthalate ester of-hydroxy-p,,odimethyl-gamma-butyrolactone is Example IV Equimolecularequivalents of strychnine and racemic hydrogen phthalate ofa-hydroxy-fl,fldimethyl-gammabutyrolactone are dissolved in warmacetone, and then concentrated until crystallizationstarts. The crystalsare filtered, recrystallized from nitrobenzene. and then from withsodium hydroxide and slums, and distilledi l The racemic a-hydroxylethanol. M. P. of the strychnine salt of the acid phthalate ester ofracemic a-hydroXy-Bfi-dimethyl-gamma-butyrolactone is ZN-208.

The corresponding quinine, quinidine, einchonine and cinchonidine saltsmay be prepared in the same manner as the strychninelsalt above.

Example V Equimolecular equivalents of the racemic hydro hours. Aftercooling and adding ice, the mixgen phthalate ester ofu-hydroxy-pp-dimethylgamma-butyrolactone and brucine aredi'ssolved in achloroform-alcohol mixture, and concentrated. As the resulting oil isstirred with several portions of petroleum ether, the productsolidifies. Upon dissolving in acetone and chilling,

the crystalline brucine salt is obtained. After M. P. iS 113-116".Example VI 556 gms. of the racemic hydrogen phthalate ester of I ahydroxy-p.cedimethyl-gamma-butyrolaetoneare treatedwith clilutejsodiumcarbonate until pH 1.2. Then, 4.1M- gms, or; ephedrine hydrochloride incc.-of. water areadded, The solution. is concentratedin vacuum at, 25extracted, with. chloroform and dried.v The oil, ob-

reorystallizing, the

the resulting oil is distilled at 178 180" under 3 mm. pressure. tainedas a colorless oil, which sets to a waxy solid on cooling.

I ExampZeVIII One hundred and two mg. of a-hydroxy-13,5-dimethyl-gamma-hutyrolactone and 201.2 mg.

of d-camphorsulfonic acid chloride are dissolved in 0.500. dry pyridine,and heated at 100 for two "time is acidified to Congo red with dilutehydrochloric acid. The precipitated product is dissolved inethen'thesolution washed with water,

and-driedover sodium sulfate. The ether is removed in vacuum, and theresidual oil crystallizes upon scratching. The .camphor sulfonate tainedafter remoyinglthe chloroform, is rubbed with ether several times, andthen with petroleum ether, which causes; the ephedrine. salt, to

,solidify,; M. F.

The same product is olotainahle by mixing ephedrine with the hydrogenphthalate ester in etheri g i- I Exam zevI-r" "Si-x and one-halt gms;oithe=racemic lactone are heated with 5 gms. of suceinic anhydridein 5cc. of dry pyridine for 2 hours at C. The

mixture is cooled, ice is" added, and the resulting'mixtureacidifiedwith dilute sulfuric acid. The

solution: then extracted with ether; and the ether extract dried over,anhydrous sodium sulfate. The; solution: is concentrated invacuaand i;Thebruciae or a-hydroXy-e,e,-dimethyl-gamma-butyrolaotone onrecrystallization from alcohol-petroleum ether mixture, forms longslender needles, M. 1?. 119-1202 I The ioregoingf examples are given, byway of illustration and not of limitation, and modifications may be madein carrying out the present invention. without departing from the spiritand scope-thereof. i Y

Iclaim;

salt. of the acid. phthalateester of racemic voz-hydroxy tgfii-methylgamma-hut? rolactone.

'2. AI'nem ber selected froth the group consisting of the hydrogenphthalate ester of; a-hydroxyfl,6edimethyl-gammaebutyrolactone, andalkaloid saltsther'eoi. g

V 3. A member selected from the group consisting of organic dibasic;acid half-esters of a-hydroxy-cp-dimethyl-gamma butyrolactone andalkaloid, salts thereof, l

4. A member selected from thegroup consist ing of the hydrogen;succinate ester of e liydroxypfi-dimethyl-gamm-a-butyrolactone, andalkaloid saltsthereof. p i U W Y t dACQB- FINKELS' EIN.

The acid succinate ester is ob- CERTIFICATE OF CORRECTION.

Patent No. 2,52 ,000. August 51, 191g.

JACOB FINKELSTEIN.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows: Page 2,sec- 0nd column, line 29, claim 1, for "methyl" read d1 ethy1--; d th tthe said Letters Patent should be read with this correction therein thatthe same may conform to the record of the caseifin the Patent Office.

Signed and sealed this 2nd day of November, A. D. 19 5- Henry VanArsdale, (Seal) Acting Commissioner of Patents.

